Poor prognosis of severe sepsis is associated with impaired microcirculation, multiple organ injury and disseminated intravascular coagulation (DIC) as a result of interdependent mechanisms of systemic intravascular inflammation, vascular leakage, microvascular thrombosis, and thrombocytopenia. Currently, no drug is available to concomitantly treat these events in sepsis. We recently discovered an important role for VWF/GPIb-IX- and integrin-dependent platelet adhesion and thrombus formation in sepsis (Yin ATVB 2013), and that G?/13 family of heterotrimeric G proteins play critical roles in integrin outside-in signaling in platelets (Gong et al, Science 2010, Shen et al Nature 2013) and in vWF secretion by endothelial cells (Rusu et al Blood 2014). G?/13 also negatively regulates cadherin function (Meigs JBC 2002) and increases endothelial permeability. In addition, we have identified NOS1-dependent regulation of Suppressor of Cytokine Signaling (SOCS1) expression in monocytes/macrophages (Baig et al, Science Signaling, in revision) as a critical determinant of sepsis-induced vascular inflammation and hyperpermeability. Here, we will test the hypotheses that sepsis can be effectively treated by concomitant anti-thrombotic, anti-inflammatory and anti- hyperpermeability therapy with novel agents that do not cause hemorrhage and vascular leakage. We have generated novel inhibitory peptides of G?/?AP interaction that inhibit endothelial VWF secretion as well as inhibitors of G?-integrin and vWF-GPIb-IX interactions that potently inhibit thrombosis without adversely inducing hemorrhage (Shen et al, Nature 2013; Yin et al, ATVB 2013; Rusu et al., Blood 2013). We propose to (1) determine the therapeutic effect of inhibiting GPIb and G?/13/integrin signaling in sepsis; (2) determine the role of G?-dependent endothelial cell VWF secretion in sepsis-induced microthrombosis; and (3) interfere with the inflammatory response that induces endothelial hyperpermeability in sepsis concomitantly with anti-thrombotic therapy. This study will not only provide novel therapeutic concepts in sepsis, but also translate these concepts into new anti-sepsis drugs and treatments.